Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
  • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
  • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J21/005—Ketals
  • C07J21/008—Ketals at position 17
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
  • C07J71/0005—Oxygen-containing hetero ring
  • C07J71/001—Oxiranes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
  • C07J71/0005—Oxygen-containing hetero ring
  • C07J71/001—Oxiranes
  • C07J71/0015—Oxiranes at position 9(11)

Definitions

• a first aspect of the invention is a compound that is: or a pharmaceutically acceptable salt or solvate thereof.
• a second aspect of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
• a third aspect of the invention is a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, for use in a method for treating cancer in a subject in need thereof.
• a fourth aspect of the invention is a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing incidences of cancer recurrence in a subject in cancer remission.
• a fifth aspect of the invention is a compound of the first aspect, or a pharmaceutically acceptable salt or solvate thereof, for use in a method for treating a chemo-resistant cancer in a subject in need thereof.
• the cancer is breast cancer.
• the cancer is ovarian cancer.
• the cancer is prostate cancer.
• the subject in need has elevated tumor glucocorticoid receptor expression.
• the cancer is triple negative breast cancer, high grade serous ovarian cancer, castration resistant prostate cancer, or doubly resistant prostate cancer.
• the cancer is castration resistant prostate cancer.
• the method further comprises administering a second therapeutic agent to the subject; wherein the second therapeutic agent is an androgen receptor inhibitor.
• the androgen receptor inhibitor is enzalutamide.
• the method further comprises administering a second therapeutic agent to the subject; wherein the second therapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin, camptothecin, topotecan, or any combinations thereof.
• the second therapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin, camptothecin, topotecan, or any combinations thereof.
• the method further comprises administering a second therapeutic agent to the subject; wherein the second therapeutic agent is nab-paclitaxel.
• the method further comprises administering a second therapeutic agent to the subject; wherein the second therapeutic agent is an anti-PD-L1 agent or an anti-PD1 agent.
• a substituted steroidal derivative compound of the following formula and pharmaceutical compositions comprising said compound.
• the compound and compositions are useful as inhibitors of glucocorticoid receptors (GR).
• GR glucocorticoid receptors
• the compound and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, lung cancer, and ovarian cancer, and hypercortisolism.
• compositions comprising a pharmaceutically acceptable excipient and the compound of the invention, or a pharmaceutically acceptable salt or solvate thereof.
• the compound of the invention for use in methods for treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof. Also provided herein is the compound of the invention for use in methods for reducing incidences of cancer recurrence, the method comprising administering to a subject in cancer remission a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof. Some embodiments provided herein describe the compound of the invention for use in methods for treating a chemo-resistant cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof.
• the cancer is triple negative breast cancer, high grade serous ovarian cancer, castration resistant prostate cancer, or doubly resistant prostate cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the methods further comprise administering a second therapeutic agent to the subject. In some embodiments, the methods further comprise administering one or more additional therapeutic agents. In some embodiments, the second or additional therapeutic agent is an androgen receptor signaling inhibitor.
• the androgen receptor signaling inhibitor is 3,3'-diindolylmethane (DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidal antiandrogens, turosteride, or any combinations thereof.
• the second or additional therapeutic agent is a chemotherapeutic agent.
• the second or additional therapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin, camptothecin, topotecan, or any combinations thereof.
• the second or additional therapeutic agent is an immunotherapy agent (e.g., an anti-PD-L1 agent or an anti-PD1 agent).
• the second or additional therapeutic agent is an anti-PD-L1 agent.
• the second or additional therapeutic agent is an anti-PD 1 agent.
• the compound of the invention for use in methods for treating a hypercortisolism disease or disorder in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof.
• the hypercortisolism disease or disorder is Cushing's syndrome.
• the hypercortisolism disease or disorder is refractory Cushing's syndrome.
• the compound of the invention may exhibit its natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compound of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
• hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature.
• Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
• Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
• the compound of the invention contains one or more isotopic variants (e.g., deuterium, tritium, 13 C, and/or 14 C).
• a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
• the compound of the invention in certain embodiments, exists as a tautomer. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
• “Pharmaceutically acceptable salt” includes both acid and base addition salts.
• a pharmaceutically acceptable salt of the compound of the invention is intended to encompass any and all pharmaceutically suitable salt forms.
• Preferred pharmaceutically acceptable salts of the compound of the invention are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
• “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
• acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
• Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
• Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
• “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
• Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N -dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N -methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N -ethylpiperidine, polyamine resins and the like. See Berge
• treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
• therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
• a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
• the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
• Table 1 lists the compound of the invention (compound #2), plus additional compounds for the purposes of comparison.
• TABLE 1 # Structure Mass, [M+H] + # Structure Mass, [M+H] + 1 500.5 2 502.4 3 489.4 4 518.5 5 475.4 6 488.5 7 516.3 8 516.5 9 502.4 10 488.4 11 516.5 12 - 13 446.3 14 506.5 15 520.4 16 516.5 17 476.4 18 486.4 19 474.4 20 529.4 21 500.5 22 564.3 23 432.4 24 557.5 25 615.3 26 418.3 27 593.4 28 498.4 29 526.3 30 460.4 31 468.4 32 -
• the substituted steroidal derivative compound as described herein is administered as a pure chemical.
• the substituted steroidal derivative compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005 )).
• composition comprising the compound of the invention, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
• the carrier(s) or excipient(s)
• the carrier is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient ( i.e., the subject) of the composition.
• One embodiment provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• the compound of the invention is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
• Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
• suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. ( See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005 )).
• the dose of the composition comprising the compound of the invention differs, depending upon the patient's (e.g ., human) condition, that is, stage of the disease, general health status, age, and other factors.
• compositions are administered in a manner appropriate to the disease to be treated (or prevented).
• An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
• an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
• Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
• Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
• Mifepristone is a non-selective modulator of several nuclear receptors. Mifepristone has been referred to as a GR antagonist, a progesterone receptor (PR) antagonist, a GR partial agonist, an androgen receptor (AR) antagonist and an AR partial agonist in the scientific literature.
• PR progesterone receptor
• AR androgen receptor
• the activity observed at multiple hormone receptors leads to various undesirable side effects and in some instances, the promotion of cancer.
• AR agonism is an undesirable feature for GR antagonists used in the treatment of cancer (e.g., AR positive or AR dependent cancers including "castration resistant" prostate cancer (CRPC), breast cancer, or ovarian cancer).
• Antagonists of GR that have minimized binding to other hormone receptors, such as the androgen receptor (AR) are needed to effectively treat the diseases described herein with reduced side effects.
• the compound of the invention that is a modulator of glucocorticoid receptors (GR).
• the compound of the invention alters the level and/or activity of GR.
• the compound of the invention is a GR inhibitor.
• the GR inhibitor is a GR antagonist.
• the glucocorticoid receptor antagonist binds to the receptor and prevents glucocorticoid receptor agonists from binding and eliciting GR mediated events, including transcription.
• the compound of the invention inhibits GR transcriptional activation activity.
• the compound of the invention is a selective GR antagonist.
• the compound of the invention is not a GR agonist. In some embodiments, the compound of the invention is not a GR partial agonist. In some embodiments, the GR inhibitor lessens cortisol activity in cells and makes secondary therapeutic agents more effective.
• GR antagonists are useful for treating or preventing weight gain (e.g., Olanzapine induced weight gain), uterine fibrosis, alcoholism, alcohol abuse disorders, cocaine dependence, bipolar depression, adrenal hypercortisolism, post-traumatic stress disorder, anxiety disorders, mood disorders, hyperglycemia, and to induce abortion.
• weight gain e.g., Olanzapine induced weight gain
• uterine fibrosis alcoholism
• alcohol abuse disorders e.g., cocaine dependence, bipolar depression, adrenal hypercortisolism
• post-traumatic stress disorder e.g., anxiety disorders, mood disorders, hyperglycemia, and to induce abortion.
• the GR inhibitor of the invention is also an androgen receptor (AR) signaling inhibitor.
• the AR signaling inhibitor is an AR antagonist.
• the AR antagonist binds to AR and prevents the AR agonist from binding and eliciting AR mediated events, including transcription.
• the GR inhibitor is not an androgen receptor (AR) signaling inhibitor. In these instances, the GR inhibitor does not significantly activate AR levels and/or activity. In some embodiments, the GR inhibitor is not an AR agonist.
• the GR inhibitor of the invention has minimized binding to the androgen receptor (AR).
• AR androgen receptor
• the compound of the invention is not an AR agonist.
• the compound of the invention is not a partial AR agonist.
• the compound of the invention has minimized partial AR agonism compared to mifepristone.
• the GR inhibitor of the invention is not a partial AR agonist or partial GR agonist.
• the GR inhibitor of the invention does not modulate progesterone receptors. In some embodiments, the GR inhibitor of the invention is not a progesterone WJW / FP7487366 - EP 17 859 300.0 - Amended Description filed December 2020 receptor (PR) inhibitor. In these instances, the GR inhibitor does not significantly activate PR levels and/or activity. In some embodiments, the GR inhibitor of the invention is not a PR agonist. In some embodiments, the GR inhibitor of the invention is not a PR partial agonist. In some embodiments, the GR inhibitor of the invention is not a PR antagonists.
• the GR inhibitor of the invention is a selective inhibitor.
• use of the GR inhibitor in a patient does not cause or result in vaginal bleeding, cramping, nausea, vomiting, diarrhea, dizziness, back pain, weakness, tiredness, or combinations thereof.
• use of the GR inhibitor in a patient does not cause or result in vaginal bleeding.
• use of the GR inhibitor in a patient does not cause or result in cramping.
• use of the GR inhibitor in a patient does not cause or result in allergic reactions, low blood pressure, loss of consciousness, shortness of breath, rapid heartbeat, or combinations thereof.
• One embodiment provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any of the Formulas provided herein, or a pharmaceutically acceptable salt thereof.
• a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., an anti-cancer agent) for treating cancer.
• the combination of the GR inhibitor with the second therapeutic agent e.g., an anti-cancer agent
• a GR inhibitor described herein is used in combination with one or more additional therapeutic agents (e.g., anti-cancer agents) for treating cancer.
• the combination of the GR inhibitor with the one or more additional therapeutic agents provides a more effective initial therapy for treating cancer compared to the one or more therapeutic agents (e.g., an anti-cancer agents) administered alone.
• the cancer is chemoresistant cancer, radio resistant cancer, or refractory cancer. In some embodiments, the cancer is relapsed cancer, persistent cancer, or recurrent cancer. Another embodiment provided herein describes a method of reducing incidences of cancer recurrence. Also provided here in some embodiments, is a method for treating a chemo-resistant cancer.
• Prostate cancer is the second most common cause of cancer death in men in the United States, and approximately one in every six American men will be diagnosed with the disease during his lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men.
• One embodiment provides a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a compound of any of the Formulas provided herein, or a pharmaceutically acceptable salt thereof.
• a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., an anti-cancer agent) for treating prostate cancer.
• the combination of the GR inhibitor with the second therapeutic agent e.g., an anti-cancer agent
• the combination of the GR inhibitor with the second therapeutic agent provides a more effective initial therapy for treating prostate cancer compared to the second therapeutic agent (e.g., an anti-cancer agent) administered alone.
• a GR inhibitor described herein is used in combination with one or more additional therapeutic agents (e.g., anti-cancer agents) for treating prostate cancer.
• the combination of the GR inhibitor with the one or more additional therapeutic agents provides a more effective initial therapy for treating prostate cancer compared to the one or more therapeutic agents (e.g., an anti-cancer agents) administered alone.
• the prostate cancer is chemoresistant cancer, radio resistant cancer, antiandrogen resistant, or refractory cancer. In some embodiments, the prostate cancer is relapsed cancer, persistent cancer, or recurrent cancer.
• the prostate cancer is acinar adenocarcinoma, atrophic carcinoma, foamy carcinoma, colloid carcinoma, or signet ring carcinoma.
• the prostate cancer is ductal adenomcarcinoma, transitional cell cancer, urothelial cancer, squamous cell cancer, carcinoid cancer, small cell cancer, sarcoma cancer, or sarcomatoid cancer.
• the prostate cancer is metastatic castration-resistant prostate cancer, doubly-resistant prostate cancer, castration-resistant prostate cancer, hormone-resistant prostate cancer, androgen-independent, or androgen-refractory cancer.
• antiandrogens are useful for the treatment of prostate cancer during its early stages.
• prostate cancer cells depend on androgen receptor (AR) for their proliferation and survival.
• AR androgen receptor
• Some prostate cancer patients are physically castrated or chemically castrated by treatment with agents that block production of testosterone (e.g. GnRH agonists), alone or in combination with antiandrogens, which antagonize effects of any residual testosterone.
• prostate cancer advances to a hormone-refractory state in which the disease progresses despite continued androgen ablation or antiandrogen therapy.
• the hormone-refractory state to which most patients eventually progresses in the presence of continued androgen ablation or anti-androgen therapy is known as "castration resistant" prostate cancer (CRPC).
• CRPC is associated with an overexpression of AR.
• AR is expressed in most prostate cancer cells and overexpression of AR is necessary and sufficient for androgen-independent growth of prostate cancer cells. Failure in hormonal therapy, resulting from development of androgen-independent growth, is an obstacle for successful management of advanced prostate cancer.
• Doubly resistant prostate cancer is characterized in that tumor cells have become castration resistant and overexpress AR, a hallmark of CRPC. However, cells remain resistant when treated with second generation antiandrogens. Doubly resistant prostate cancer cells are characterized by a lack of effectiveness of second generation antiandrogens in inhibiting tumor growth.
• resistant prostate cancer e.g., doubly resistant and castration resistant prostate cancers
• AR androgen receptors
• AR target gene expression is inhibited when the cells are treated with a second generation antiandrogen.
• increased signaling through the glucocorticoid receptor (GR) compensates for inhibition of androgen receptor signaling in resistant prostate cancer.
• Double resistant prostate cancer develops when expression of a subset of those AR target genes is restored.
• GR activation is responsible for this target gene activation.
• GR transcription is activated in patients susceptible to or suffering from resistant prostate cancer (e.g., doubly resistant and castration resistant prostate cancers).
• GR upregulation in cancer cells confers resistance to antiandrogens.
• Some embodiments provided herein describe the use of the GR inhibitors for treating prostate cancer in a subject in need thereof, including doubly resistant prostate cancer and castration resistant prostate cancer.
• the subject in need has elevated tumor GR expression.
• the GR inhibitor is also an AR signaling inhibitor or antiandrogen.
• the GR inhibitor is used in combination with a second therapeutic agent. In some embodiments, the GR inhibitor is used in combination with one or more additional therapeutic agents. In some embodiments, the second or additional agent is an anti-cancer agent. In certain embodiments, the anti-cancer agent is useful for AR positive or AR negative prostate cancer.
• the second or additional agent is an AR signaling inhibitor or antiandrogen.
• the AR signaling inhibitor is an AR antagonist.
• the second or additional therapeutic agent is selected from finasteride, dutasteride, alfatradiol, cyproterone acetate, spironolactone, danazol, gestrinone, ketoconazole, abiraterone acetate, enzalutamide, ARN-509, danazol, gestrinone, danazol, simvastatin, aminoglutethimide, atorvastatin, simvastatin, progesterone, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, drospirenone, estradiol, ethinyl estradiol, diethylstilbestrol, conjugated equine estrogens, bus
• the second or additional therapeutic agent is selected from flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, cimetidine, or any combinations or any salts thereof.
• the AR signaling inhibitor is 3,3'-diindolylmethane (DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidal antiandrogens, turosteride, or any combinations thereof.
• the AR signaling inhibitor is flutamide, nilutamide, bicalutamide, or megestrol.
• the AR signaling inhibitor is ARN-509. In other embodiments, the AR signaling inhibitor is enzalutamide.
• the anti-cancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin.
• the anti-cancer agent is paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin.
• the anti-cancer agent is docetaxel.
• Breast cancer is the second leading cause of cancer among women in the United States. Triple-negative breast cancers are among the most aggressive and difficult to treat of all the breast cancer types. Triple-negative breast cancer is a form of the disease in which the three receptors that fuel most breast cancer growth - estrogen, progesterone and the HER-2 - are not present. Because the tumor cells lack these receptors, treatments that target estrogen, progesterone and HER-2 are ineffective. Approximately 40,000 women are diagnosed with triple-negative breast cancer each year. It is estimated that more than half of these women's tumor cells express significant amounts of GR.
• GR expression is associated with a poor prognosis in estrogen receptor (ER)-negative early stage breast cancer.
• ER estrogen receptor
• GR activation in triple-negative breast cancer cells initiates an anti-apoptotic gene expression profile that is associated with inhibiting chemotherapy-induced tumor cell death.
• GR activity in these cancer cells correlate with chemotherapy resistance and increased recurrence of cancer.
• a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating breast cancer.
• a second therapeutic agent e.g., a chemotherapeutic agent
• the combination of the GR inhibitor with the second therapeutic agent e.g., a chemotherapeutic agent
• a GR inhibitor described herein is used in combination with one or more additional therapeutic agents (e.g., anti-cancer agents) for treating breast cancer.
• the combination of the GR inhibitor with the one or more additional therapeutic agents provides a more effective initial therapy for treating breast cancer compared to the one or more therapeutic agents (e.g., an anti-cancer agents) administered alone.
• the breast cancer is chemoresistant cancer, radio resistant cancer, or refractory cancer. In some embodiments, the breast cancer is relapsed cancer, persistent cancer, or recurrent cancer.
• Breast cancers may include, but are not limited to, ductal carcinoma, invasive ductal carcinoma, tubular carcinoma of the breast, medullary carcinoma of the breast, mecinous carcinoma of the breast, papillary carcinoma of the breast, cribriform carcinoma of the breast, invasive lobular carcinoma, inflammatory breast cancer, lobular carcinoma in situ, male breast cancer, Paget disease of the nipple, phyllodes tumor of the breast, recurrent and metastatic breast cancer, triple-negative breast cancer, or combinations thereof.
• the breast cancer is recurrent and metastatic breast cancer, triple-negative breast cancer, or combinations thereof.
• the breast cancer is chemoresistant triple-negative breast cancer or estrogen receptor (ER) negative breast cancer.
• the breast cancer is chemoresistant triple-negative breast cancer.
• the breast cancer is estrogen receptor (ER) negative breast cancer.
• the breast cancer is GR+ triple-negative breast cancer.
• the breast cancer is GR+ estrogen receptor (ER) negative breast cancer.
• GR inhibitors for treating breast cancer in a patient, including triple negative breast cancer or ER negative breast cancer.
• GR inhibitors inhibit the anti-apoptotic signaling pathways of GR and increase the cytotoxic efficiency of secondary chemotherapeutic agents.
• the GR inhibitors described herein enhance the efficacy of chemotherapy in breast cancer patients, such as triple negative breast cancer patients.
• the breast cancer patient has elevated tumor GR expression.
• a GR inhibitor described herein is used in combination with a second therapeutic agent, such as chemotherapy or immunotherapy.
• a GR inhibitor described herein is used in combination with one or more additional therapeutic agents.
• the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, daunorubicin, fluorouracil, mitomycin, thiotepa, vincristine,
• the second or additional therapeutic agent is an anti-PD-L1 agent.
• the anti-PD-L1 agent is MPDL3280A or avelumab.
• the second or additional therapeutic agent is an anti-PD 1 agent.
• the anti-PD 1 agent is nivolumab or permbrolizumab.
• Some embodiments provided herein describe methods of treating estrogen positive breast cancer.
• estrogen positive breast cancer patients become resistant to estrogen receptor modulators.
• the GR inhibitors described herein enhance the efficacy of estrogen receptor modulators in estrogen positive breast cancer patients.
• the breast cancer patient has elevated tumor GR expression.
• a GR inhibitor described herein is used in combination with an estrogen receptor modulator.
• the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, fulvestrant, lasofoxifene, clomifene, ormeloxifene, or ospemifene.
• the estrogen receptor modulator is tamoxifen, raloxifene, toremifene, tibolone, or fulvestrant. In some embodiments, the estrogen receptor modulator is tamoxifen, raloxifene, or toremifene. In certain embodiments, the estrogen receptor modulator is tamoxifen.
• Ovarian cancer is the leading cause of death from gynecologic malignancies.
• Some ovarian cancers e.g., high grade serous ovarian cancer
• platinum-based therapy but relapse rates remain high.
• One embodiment provides a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a compound of any of the Formulas provided herein, or a pharmaceutically acceptable salt thereof.
• the patient has elevated tumor GR expression.
• a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating ovarian cancer.
• the combination of the GR inhibitor with the second therapeutic agent e.g., a chemotherapeutic agent
• the second therapeutic agent e.g., a chemotherapeutic agent
• a GR inhibitor described herein is used in combination with one or more additional therapeutic agents (e.g., anti-cancer agents) for treating ovarian cancer.
• the combination of the GR inhibitor with the one or more additional therapeutic agents provides a more effective initial therapy for treating ovarian cancer compared to the one or more therapeutic agents (e.g., an anti-cancer agents) administered alone.
• GR activation increases resistance to chemotherapy in ovarian cancer (e.g., high-grade serous ovarian cancer). In some instances, GR activation significantly inhibits chemotherapy induced apoptosis in ovarian cancer cells.
• a GR inhibitor e.g., GR antagonist
• the ovarian cancer has become resistant to chemotherapy.
• the ovarian cancer cells are resistant to cisplatin, paclitaxel, carboplatin, gemcitabine, alone or in combination.
• the GR inhibitor or antagonist reverses the cell survival effect.
• Ovarian cancers may include, but are not limited to, epithelial ovarian cancers, such as serous epithelial ovarian cancer, endometrioid epithelial ovarian cancer, clear cell epithelial ovarian cancer, mucinous epithelial ovarian cancer, undifferentiated or unclassifiable epithelial ovarian cancer, refractory ovarian cancer, sex cord-stromal tumors, Sertoli and Sertoli-Leydig cell tumors, germ cell tumors, such as dysgerminoma and nondysgerminomatous tumors, Brenner tumors, primary peritoneal carcinoma, fallopian tube cancer, or combinations thereof.
• epithelial ovarian cancers such as serous epithelial ovarian cancer, endometrioid epithelial ovarian cancer, clear cell epithelial ovarian cancer, mucinous epithelial ovarian cancer, undifferentiated or unclassifiable epithelial
• the GR inhibitor is used in combination with at least a second therapeutic agent, such as chemotherapy or immunotherapy.
• the GR inhibitor is used in combination with one or more additional therapeutic agents.
• the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, daunorubicin, fluorouracil, mitomycin, thiotepa, vincristine, everolimus, ve
• the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. In some embodiments, the second or additional therapeutic agent is an anti-PD-L1 agent. In certain embodiments, the anti-PD-L1 agent is MPDL3280A or avelumab. In some embodiments, the second or additional therapeutic agent is an anti-PD 1 agent. In certain embodiments, the anti-PD 1 agent is nivolumab or permbrolizumab.
• One embodiment provides a method of treating non-small cell lung cancer (NSCLC) in a patient in need thereof, comprising administering to the patient a compound of any of the Formulas provided herein, or a pharmaceutically acceptable salt thereof.
• the patient has elevated tumor GR expression.
• a GR inhibitor described herein is used in combination with a second therapeutic agent (e.g., a chemotherapeutic agent) for treating NSCLC.
• the combination of the GR inhibitor with the second therapeutic agent e.g., a chemotherapeutic agent
• a GR inhibitor described herein is used in combination with one or more additional therapeutic agents (e.g., anti-cancer agents) for treating NSCLC.
• the combination of the GR inhibitor with the one or more additional therapeutic agents provides a more effective initial therapy for treating NSCLC compared to the one or more therapeutic agents (e.g., an anti-cancer agents) administered alone.
• the GR inhibitor is used in combination with at least a second therapeutic agent, such as a chemotherapeutic agent or immunotherapy.
• the GR inhibitor is used in combination with one or more additional therapeutic agents.
• the second or additional chemotherapeutic agent is cisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin, melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine, daunorubicin, fluorouracil, mitomycin, thiotepa,
• the second or additional chemotherapeutic agent is gemcitabine. In some embodiments, the second or additional chemotherapeutic agent is carboplatin. In some embodiments, the second or additional chemotherapeutic agent is cisplatin. In some embodiments, the second or additional agent is paclitaxel. In some embodiments, the GR inhibitor is used in combination with gemcitabine and carboplatin. In some embodiments, the GR inhibitor is used in combination with carboplatin and cisplatin. In some embodiments, the second or additional therapeutic agent is an anti-PD-L1 agent. In certain embodiments, the anti-PD-L1 agent is MPDL3280A or avelumab. In some embodiments, the second or additional therapeutic agent is an anti-PD 1 agent. In certain embodiments, the anti-PD 1 agent is nivolumab or permbrolizumab.
• One embodiment provides a method of treating hypercortisolism or Cushing's disease in a patient in need thereof, comprising administering to the patient a compound of any of the Formulas provided herein, or a pharmaceutically acceptable salt thereof.
• Types of Cushing's disease include, but are not limited to, recurrent Cushing's disease, refractory Cushing's disease, persistent Cushing's disease, endogenous Cushing's disease, spontaneous hypercortisolism, Adrenocorticotropic hormone dependent, Adrenocorticotropic hormone independent, or combinations thereof.
• Causes of hypercortisolism may include, but are not limited to, prolonged exposure to cortisol, a tumor that produces excessive cortisol, a tumor that results in the excess production of cortisol, or combinations thereof.
• Example 10 is according to the invention; all other examples are included for the purposes of comparison only.
• Adrenosterone (50.2 g, 1 eq) was dissolved in 390 ml DCM with 91 g of trimethylorthoformate (5.2 eq) and 119 g of ethylene glycol (11.5 eq). Toluenesulfonic acid (1.9 g, 0.06 eq) was added. The reaction was heated to 40 °C for 18 h. The dark colored solution was quenched with 4 ml pyridine. The reaction was concentrated to remove solvents. The residue was taken up in DCM and washed with water. The organic layer was dried with MgSO 4 , filtered and concentrated to give 74.3 g of a mushy solid. The solid was purified to give 42.2 g (65%) of the title compound. m/z (ESI, +ve ion) 389.3 (M+H) + .
• STEP B (8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9',10',13',14',15',16'-decahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2"-[1,3]d l oxolan]-11'-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate
• Lithium diisopropylamide solution was prepared as follows. In an oven-dried 500 mL flask a solution of 125 mL THF and anhydrous diisopropylamine (5.77 mL, 4.1 eq) was cooled in a dry ice-acetone bath. N -butyl lithium (25.1 mL, 4 eq, 1.6 M in hexanes) was added slowly and the reaction was stirred for 25 min. A separate flask was charged with the starting bis-ketal (Step A) (3.9 g, 1 eq), azeotroped with toluene, dried under vacuum, flushed with Ar and kept under an Ar balloon.
• Step A the starting bis-ketal
• Step C tert-Butyl (4-((8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9',10',13',14',15',16'-decahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2"-[1,3]dioxolan]-11 '-yl)phenyl)(methyl)carbamate
• Step B (1.4 g, 1 eq), (4-((tert-butoxycarbonyl)(methyl)amino)phenyl)boronic acid (5.2 g, 10 eq), lithium chloride (177 mg, 2 eq), and Pd(PPh 3 ) 4 (193 mg, 0.08 eq).
• Step D tert-Butyl (4-((4a'R,5a'S,6a'S,6b'S,9a'R,11a'R,11b'R)-9a',1 1b'-dimethyl-1',5a',6',6a',6b',7',8',9a',11a',11b'-decahydro-2'H,4'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[1,2]phenanthro[8a,9-b]oxirene-9',2"-[1,3]dioxolan]-11'-yl)phenyl)(methyl)carbamate
• Step C (520 mg, 0.9 mmol) in DCM (10 mL) at 0°C was added 1,1,1,3,3,3-hexafluoropropan-2-one (0.14 mL, 0.99 mmol), followed by 30% hydrogen peroxide aqueous solution (0.37 mL, 4.5 mmol) and disodium phosphate (383.3 mg, 2.7 mmol).
• reaction mixture was stirred at 0°C for 10 min and rt overnight. Additional aliquots of reagents (380 mg of disodium phosphate, 0.13 mL of CF 3 COCF 3 , 0.35 mL of 30% H 2 O 2 ) were added at 24 h and 48 h time points. The reaction was quenched with 10% Na 2 S 2 O 3 solution and extracted with EtOAc. After washing with brine, the organic layer was separated, dried with MgSO 4 and concentrated. The residue was purified by silica gel chromatography to provide 470 mg (88%) of desired epoxide as a white foamy solid.
• Step E tert-Butyl (4-((5'R,8'S,9'R,10'R,13'R,14'S)-5'-hydroxy-10',13'-dimethyl-1',4',5',6',7',8',9',10',13',14',15',16'-dodecahydro-2'H-dispiro[[1,3]dloxolane-2,3'-cyclopenta[a]phenanthrene-17',2"-[1,3]dioxolan]-11 '-yl)phenyl)(methyl)carbamate
• STEP F tert-Butyl (4-((3a'S,3b'S,5a'R,9a'R,9b'S,9c'R,10a'R,10b'R)-5a'-hydroxy-9a',10b'-dimethyltetradecahydro-9c'H-dispiro[[1,3]dioxolane-2,1'-cyclopenta[1,2]phenanthro[3,4-b]oxirene-7',2"-[1,3]dioxolane]-9c'-yl)phenyl)(methyl)carbamate
• the reaction was stirred at rt for 20 h and treated with sat. NaHCO 3 , and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of 0-45% EtOAc in hexanes to provide the more polar isomer (530 mg, 27%) as the desired product. The less polar isomer was also isolated (910 mg, 46%).
• STEP G (5'R,8'S,9'R,10'R,11'S,12'S,13'R,14'S)-10',13'-Dimethyl-11'-(4-(methylamino)phenyl)dodecahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2"-[1,3]dioxolane]-5',12'( 4'H)-diol
• STEP K (8S,9R, 10R 11S, 13S,14S)-11-(4-(Dimethylamino)phenyl)-10, 13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione
• Step J O-((8S,9R,10R,12S,13R,14S)-11-(4-(dimethylamino)phenyl)-10,13-dimethyl-3,17-dioxo-2,3,6,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-12-yl) 1H-imidazole-1-carbothioate (Step J) (420 mg, 0.79 mmol) and flushed with argon. Toluene (19mL) was added, followed by tributyltin hydride (0.42mL, 1.58 mmol).
• Step K (210.mg, 0.52 mmol) and azeotroped with toluene.
• p-Toluenesulfonic acid monohydrate (118.2 mg, 0.62 mmol) was added to the flask and the flask was flushed with Argon.
• STEP M (8S,9R,10R,11S,13S,14S,17S)-11-(4-(Dimethylamino)phenyl)-17-hydroxy-17-(3-methoxyprop-1-yn-1-yl)-10, 13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one
• STEP B (5'R,8'S,10'R,13'S,14'S)-13'-Methyl-1',2',7',8',12',13',14',15',16',17'-decahydro-4'H,6'H-spiro[[1,3]dioxolane-2,3'-[5,10]epoxycyclopenta[a]phenanthren]-17'-ol
• a dried flask was charged with magnesium chips (2.04 g, 83.9 mmol) and a crystal of iodine.
• the flask was flushed with Ar and heated briefly with a heat gun and then put into a 60 °C of oil bath.
• the Grignard reagent prepared above was cooled down to rt and added to a solution of (5'R,8'S,10'R,13'S,14'S)-13'-methyl-1',2',7',8',12',13',14',15',16',17'-decahydro-4'H,6'H-spiro[[1,3]dioxolane-2,3'-[5,10]epoxycyclopenta[a]phenanthren]-17'-ol (9.00 g, 27.1 mmol, azeotroped with toluene, Step B) and copper(I) iodide (2.60 g, 13.5 mmol) in THF (100 mL) at 0°C.
• STEP F (8R,9S,10R,11S,13S,14S)-11-(4-(Diethylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan] -17 -ol
• the Grignard reagent was cooled to 0 °C and a solution of (8R,9S,10R,11S,13S,14S)-11-[4-(diethylamino)phenyl]-13-methyl-spiro[1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,2'-1,3-dithiolane]-17-one (100 mg, 0.20 mmol, Step G) in THF (2 mL) was added dropwise. After the reaction was stirred at 0 °C for 30 min, it was allowed to warm to rt and stirred overnight. The reaction was quenched (sat. aq.
• Examples 3-10 were prepared by procedures similar to those described in Example 2, substituting 4-bromo-N,N-diethylaniline with the appropriate bromide in Step C and 3,3-dimethylbut-1-yne with the appropriate alkyne in Step H.
• Example 10 Compound 2. (8R,9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one
• Step A (8S,11R,13S,14S)-11-(4-Aminophenyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
• Step B tert-Butyl (4-((8S,1 1R,13S,14S)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate
• Step C (8R,9S,10R,11S,13S,14S)-11-(4-Ammophenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]-17-ol
• Step D (8R9S,10R,11S,13S,14S)-11-(4-(Isopropylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]-17-ol
• Step E (8R9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropylammo)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one
• the title compound was prepared from (8R,9S,10R,11S,13S,14S)-11-(4-(isopropylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]-17-ol (Step D) by procedures similar to those described in Example 2, Steps G, H, and I.
• Step A tert-Butyl (4-((8R,9S,10R,11S,13S,14S)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]-11 -yl)phenyl)carbamate
• Step B tert-Butyl (4-((8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,9,10, 11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate
• Step C (8R,9S,10R,11S,13S,14S,17S)-11-(4-Aminophenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3 -one
• Step A (8R,9S,10R,11S,13S,14S,16R)-1 1-(4-(Isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]-17(2H)-one or (8R,9S,10R,11S,13S,14S,16S)-1 l-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dithiolan]-17(2H)-one
• Step B (8R,9S,10R,11S,13S,14S,16R,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one or (8R,9S,10R,11S,13S,14S,16S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one
• Example 15 was prepared from (8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9',10',13',14',15',16'-decahydro-2'H-dispiro[[1,3]dioxolane-2,3'-cyclopenta[a]phenanthrene-17',2"-[1,3]dioxolan]-11'-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Example 1, Step B) by procedures similar to those described in Example 1, Steps C-M, substituting formaldehyde with acetone in Step H and substituting 3-methoxyprop-1-yne with ethynylcyclopropane in Step M.
• Example 16 was prepared from (8'S,9'S,10'R,13'R,14'S)-10',13'-dimethyl-1',4',7',8',9',10',13',14',15',16'-decahydro-2'H-dispiro[[1,3]dloxolane-2,3'-cyclopenta[a]phenanthrene-17',2"-[1,3]dioxolan]-11'-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Example 1, Step B) by procedures similar to those described in Example 1, Steps C-G, substituting (4-((tert-butoxycarbonyl)(methyl)amino)phenyl)boronic acid with (4-((tert-butoxycarbonyl)aminophenyl)boronic acid in Step C, and followed by procedures similar to those described in Example 1, Steps I-M, substituting 3-methoxyprop-1
• Example 17 was prepared from 8S,9R,10R,11S,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (Example 16) by procedure similar to that described in Example 1, Step H, substituting formaldehyde with acetone.
• Reference Example 18 Compound 31. (8S,9R,10R,11S,13S,14S,17S)-11-(4-(1H-Pyrrol-1-yl)phenyl)-17-hydroxy-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one
• Example 18 was prepared from 8S,9R,10R,11S,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (Example 16) by procedure similar to that described in Example 1, Step H, substituting formaldehyde with 2,5-dimethoxytetrahydrofuran.
• Example A In Vivo GR Luciferase Assay
• a 1 x 10cm plate of cells was split into 2 x 15cm plates in Assay Media (CSS). After 4 days, the cells in the Assay Media were collected and counted.
• the plates were covered with film to avoid evaporation and placed in a TC incubator.
• Media/drug dilutions were prepared in Assay Media in 96-well sterile plates.
• Assay Media 100ul of Assay Media was distributed in aliquots into 96-well plates with an 8-Channel pipette (20-200ul). 0.5ul of 1000X concentration of compounds were added to the plates with 8-Channel pipette (0.5-10ul). The plates were shaken for 15 seconds to mix. The film was removed from the 384-well plates with assay cells. 5ul of media/drug dilutions were added to appropriate wells. The plates were covered with film to avoid evaporation and placed in a TC incubator overnight. After 16-18 h in the incubator, the plates were removed and sat at room temperature for 10 minutes to equilibrate.
• the Reagent Dispenser was setup to distribute 25ul aliquots of OneGlo Luciferase Reagent (at room temperature) to each well of the 384-well plate using standard cassette. After OneGlo was added to the plates, the plates were shaken briefly, then incubated in the dark at room temperature for about 3 minutes. The plates were read using a Tecan or Promega luminometer.
• the AR agonism assay was done in the LNAR reporter cell line which has overexpressed AR and 4XARE-Luc genes. This cell line is sensitive to even minor partial AR agonism activity in hormone-deprived media (CSS).
• the assays were done in RPMI (without phenol red) +10% CSS using 6000 LNAR cells/well in 384-well plates and compounds were incubated with cells in 370C incubator for 18-24hrs.
• OneGlo reagent 25uL/well was added and plates were read with luminometer within 3 minutes.
• Mifepristone shows strong partial AR agonism in concentrations as low as 10 nM, and is known to significantly promote CRPC growth both in vivo and in vitro.
• Mifepristone is included as a standard in the assay.
• AR agonism assay results are quantified by determining the ratio of the maximum response of individual compounds to the maximum response of Mifepristone (arbitrarily set to 1). Values of Table 4 are reported as Relative Maximum Response to Mifepristone. This general trend of AR agonism was shown for the class of compounds described herein. TABLE 4 No.
• AR agonism response assay data relative maximum response to Mifepristone is designated within the following ranges: A: ⁇ 0.4 B: > 0.4

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